Method for the treatment of prostate cancer

ABSTRACT

A method for the treatment of advanced prostate cancer comprises administering to a patient suffering from advanced prostate cancer an androgen suppressing amount of a luteinizing hormone releasing hormone agonist analog and an amount of calcitriol sufficient to enhance the effectiveness of the luteinizing hormone releasing hormone agonist analog against the cancer relative to treatment with the luteinizing hormone releasing hormone agonist analog alone. Preferably the calcitriol is in the form of a stabilized, injectable solution of calcitriol in isotonic saline containing about 1 to about 30 milligrams per milliliter of calcitriol and a sufficient quantity of nonionic surfactant to solubilize the calcitriol therein. Preferably the a luteinizing hormone releasing hormone agonist analog is a nonapeptide or decapeptide agonist, such as leuprolide, goserelin or salts thereof. The method of the present invention affords a surprisingly improved efficacy for treatment of advanced prostate cancer such as androgen-independent prostate cancer (AIPC) or hormone refractory prostate cancer (HRPC) in comparison to treatment with a luteinizing hormone releasing hormone agonist analog alone.

FIELD OF THE INVENTION

The invention relates to a method for the treatment of prostate cancer.More particularly, this invention relates to a method for the treatmentof prostate cancer utilizing 1α,25-dihydroxycholecalciferol (calcitriol)in combination with a luteinizing hormone releasing hormone agonistanalog.

BACKGROUND OF THE INVENTION

Adenocarcinoma of the prostate gland is the most commonly diagnosedmalignancy in American men. Although prostate carcinoma is usually aslow growing malignancy, this disease caused considerable mortality.Since prostate cancer rate increases with advancing age, this diseasewill become an even greater problem as life expectancy increases.Androgens, such as testosterone, regulate the growth, differentiation,and rate of apoptosis in the prostate and its malignancies. Typicaltherapies for advanced-stage prostate cancer involve androgen withdrawalcombined with an androgen receptor antagonist. Such treatments oftenresult in initial tumor regression, but does little to alter theultimate course of the disease, since androgen-independent tumorprogression (also known as hormone refractory prostate cancer) generallyensues within an average of about 17 months. The average survivalduration for patients with metastatic prostate cancer is about 2.5 toabout 3.5 years. Nearly all patients who die of prostate cancer die fromthe hormone refractory form of the disease. Currently there is notreatment that is effective in producing prolonged survival in patientswith hormone refractory prostate cancer.

Calcitriol (1α,25-dihydroxycholecalciferol) is a biologically activeform of vitamin D₃. Calcitriol is important in intestinal calciumtransport and bone calcium resorption. An injectable solution containingabout 1 to 2 micrograms per milliliter of calcitriol has been used as atreatment for abnormal serum calcium levels. Peehl et al., Journal ofUrology, 2002; 168:1583-1588 (herein after “Peehl et al.”), havereported that calcitriol is effective at inhibiting prostate cancer cellgrowth. Pheel et al. also reported that calcitriol is particularlyeffective in conjunction with the drug ketoconazole for the treatment ofprostate cancer. Oral calcitriol has also been studied in conjunctionwith docetaxel for the treatment of androgen-independent prostatecancer. See Beer et al. Journal of Clinical Oncology, 2003;21(1):123-128.

Luteinizing hormone releasing hormone (LHRH agonist analogs are know tobe effective in the treatment of prostate cancer. For example, thesynthetic LHRH agonist analogs leuprolide and goserelin are potentinhibitors of gonadotropin secretion. Inhibition of gonadotropin resultsin an inhibition of testosterone production by the testes, and isbeneficial in the treatment of prostate cancer.

There is an ongoing need for improved treatments for advanced prostaticcancer such as androgen-independent prostate cancer. The method of thepresent invention fulfills this need.

DETAILED DESCRIPTION OF THE INVENTION

A method for the treatment of advanced prostate cancer (APC), such asmetastatic androgen-independent prostate cancer comprises administeringto a patient having APC an androgen suppressing amount of a luteinizinghormone releasing hormone (LHRH) agonist analog and an amount ofcalcitriol sufficient to enhance the effectiveness of the LHRH agonistanalog against the cancer relative to treatment with the LHRH agonistanalog alone. Preferably, the calcitriol and LHRH agonist analog areadministered parenterally as separate injections.

Preferably the LHRH agonist analog is a nonapeptide or decapeptidehaving the structure (I):

(I) 5-oxo-L-Pro-L-His-L-Trp-L-Ser-L-Tyr-Xaa-L-Leu-L-Arg-Yaa (SEQ ID NO:1), wherein Xaa is a D-amino acid residue or a modified D-amino acidresidue; and Yaa is a modified proline residue, such asN-ethyl-L-prolinamide and the like; or a dipeptide comprising a prolineand a modified glycine residue, such as L-prolylcarbazamide(Pro-Azgly-NH₂), L-prolylglycinamide (Pro-Gly-CONH₂), and the like.

Preferably, Xaa is a residue selected from the group consisting ofO-t-butyl-D-Ser, D-Leu, D-Trp, 2-methyl-D-Trp, N-benzyl-D-His, and3-(2-naphthyl)-D-Ala. Preferably, Yaa is a residue selected from thegroup consisting of N-ethyl-L-prolinamide, L-prolylcarbazamide,L-prolylglycinamide, and N-ethylprolylglycinamide.

Suitable LHRH agonist analogs include leuprolide, goserelin,triptorelin, meterelin, buserelin, histrelin, and nafarelin, and saltsthereof, which are described in U.S. Pat. No. 6,337,318 to Trigg et al.,the relevant disclosures of which are incorporated herein by reference.Preferred LHRH agonist analogs for use in the present invention includeleuprolide, goserelin, and salts thereof, such as acetate salts.

Leuprolide is a nonapeptide LHRH agonist analog having the chemicalstructure (I) wherein Xaa is a D-leucine residue and Yaa is anN-ethyl-L-prolinamide residue. See e.g., U.S. Pat. Nos. 4,005,063,4,005,194, 4,652,441, 4,677,191, and 5,716,640, which are incorporatedherein by reference.

Goserelin is a decapeptide LHRH agonist analog of structure (I) in whichXaa is an O-tert-butyl-D-serine residue and Yaa is aL-prolyl-carbazamide residue (Pro-Azgly) residue.

Triptorelin is a decapeptide LHRH agonist analog of structure (I) inwhich Xaa is a D-tryptophane residue and Yaa is a L-prolylglycinamideresidue (Pro-Gly-CONH₂) residue.

Meterelin is a nonapeptide LHRH agonist analog of structure (I) in whichXaa is a 2-methyl-D-tryptophane residue and Yaa is anN-ethyl-L-prolinamide residue.

Buserelin is a nonapeptide LHRH agonist analog of structure (I) in whichXaa is an O-tert-butyl-D-serine residue and Yaa is aN-ethyl-L-prolinamide residue.

Histrelin is a nonapeptide LHRH agonist analog of structure (I) in whichXaa is a N-benzyl-D-histidine residue and Yaa is anN-ethyl-L-prolinamide residue.

Nafarelin is a decapeptide LHRH agonist analog of structure (I) in whichXaa is a 3-(2-naphthyl)-alanine residue and Yaa is anN-ethyl-L-prolylglycinamide residue.

The calcitriol is in the form of an injectable solution and isadministered in a dosage of about 0.1 to about 20 micrograms perkilogram per week (mcg/Kg/week), most preferably about 0.5 to about 10mcg/Kg/week, based on the patient's weight in kilograms. Preferably thecalcitriol is administered as a weekly dose. A typical weekly dose is inthe range of about 0.1 to about 20 micrograms (mcg) of calcitriol for anadult patient. Alternatively a depot formulation of calcitriol can beused to provide a sustained release of calcitriol over an extendedperiod of time.

An injectable solution of calcitriol preferably comprises about 1 toabout 30 mcg/mL of calcitriol in an isotonic saline medium and asufficient quantity of nonionic surfactant to solubilize the calcitrioltherein. A preferred nonionic surfactant is a polysorbitan, such aspolysorbate-20. Preferably the polysorbitan is present in the solutionin an amount sufficient to solubilize the calcitriol, most preferably inthe range of about 5 to about 20 mg/mL.

In a preferred embodiment, the injectable solution of calcitriol alsoincludes about 1 to about 15 mg/mL of ascorbic acid, more preferablyabout 2 to about 6 mg/mL of ascorbic acid.

The injectable solution can also include about 1 to about 2 mg/mL ofethylenediamine tetraacetic acid (EDTA) or a salt thereof, such as asodium salt.

In a particularly preferred embodiment, the injectable solution ofcalcitriol includes about 5 to about 30 mcg/mL of calcitriol, about 1 toabout 15 mg/mL of ascorbic acid, and about 1 to about 2 mg/mL ofethylenediamine tetraacetic acid or a salt thereof, in an isotonicsaline medium; and a sufficient quantity of nonionic surfactant tosolubilize the calcitiriol therein.

The LHRH agonist analog is preferably administered in a mannerconventional for the particular analog in the treatment of prostateconcer.

Leuprolide, when utilized is administered preferably as an injectablesolution of leuprolide acetate or an injectable depot formulation (i.e.,sustained release subcutaneous or intramuscular preparation) ofleuprolide (free peptide form) in a physiologically acceptable carriertherefor. Leuprolide acetate is commercially available as an injectablesolution in isotonic saline. Leuprolide also can be utilized as depotformulations for sustained-release, and can be administeredsubcutaneously or intramuscularly. When leuprolide acetate isadministered as a solution, the dosage is preferably about 1 mg ofleuprolide acetate per day, subcutaneously, for a typical adult patient.

Leuprolide (free peptide) is commercially available in sustained-releasedepot formulations typically comprising, for example, leuprolide,gelatin, lactic acid/glycolic acid copolymers, D-mannitol, asmicrospheres, which are reconstituted by dilution with a solution ofsodium carboxymethylcellulose, D-mannitol and polysorbate-80 in sterileUSP water. Depot formulations of leuprolide are available in a unitdoses in the range of about 3.75 mg to 30 mg of leuprolide, for example,as a 3.75 mg weekly depot formulation, a 7.5 mg weekly or monthly depotformulation, a 11.25 mg three-month depot formulation, a 22.5 mgthree-month depot formulation, and a 30 mg four-month depot formulation.

When a commercially available 7.5 mg depot formulation of leuprolide isutilized, the dosage is preferably about 7.5 mg of leuprolide,administered by as a single intramuscular injection on a weekly ormonthly basis. Alternatively, when leuprolide is administered as a 11.25mg depot formulation the patient receives about 11.25 mg of the depotformulation as a single intramuscular injection every 3 months; whenleuprolide is administered as a 22.5 mg depot formulation the patientreceives about 22.5 mg of the depot formulation as a singleintramuscular injection every 3 months; or when leuprolide isadministered as a 30 mg depot formulation the patient receives about 30mg of the depot formulation as a single intramuscular injection every 4months. Leuprolide can also be delivered in the form of an implantablesustained release formulation, for example, as a subcutaneous implantdelivering a total dose of about 65 mg of leuprolide over a one yearperiod.

Sustained release formulations of leuprolide are available from TAPPharmeceuticals Products, Inc., Lake Forest, Ill. under the trade nameLUPRON DEPOT®, and from Sanofi Synthelabo, Inc., Malvern, Pa. under thetradename ELEGARD™. An implantable, one-year sustained releaseformulation of leuprolide acetate (about 65 mg of leuprolide free baseper unit dose) is available from Bayer Corp., Pharmeceutical Division,West Haven, Conn., under the trade name VIADUR®.

Goserelin is commercially available as the acetate salt. Goserelinacetate is available from AstraZenica Pharmaceuticals LP, under thetradename ZOLADEX®. ZOLADEX is available as 3.6 mg one-month, and 10.8mg 3-month sustained release, subcutaneously implantable formulations ofgoserelin acetate in a biodegradable D,L-lactic acid-glycolic acidcopolymer matrix.

As used herein, the term “enhanced effectiveness” and grammaticalvariations thereof, in relation to the effectiveness of leuprolide as aprostate cancer treatment includes such effects as enhancement ofandrogen suppressing activity, diminution of side effects, enhancedpatient survivability over time, reduced androgen-independent prostatetumor growth, and like effects that improve the clinical utility of LHRHagonist analogs or the quality of life of the patient.

The method of the present invention comprises administering a LHRHagonist analog in conjunction with calcitriol and affords a surprisinglyimproved efficacy for treatment of advanced prostate cancer such asandrogen-independent prostate cancer in comparison with LHRH agonistanalog treatment alone. The method of the invention prolongs andenhances the effectiveness of LHRH agonist analogs as a treatment foradvanced prostate cancer.

While parenteral administration of calcitriol is preferred, other dosageforms and routes of administration can also be utilized when practicingthe present invention. Illustrative such other dosage forms are tablets(oral, sublingual, or buccal), capsules, and the like for oraladministration, transdermal patches for percutaneous administration,solutions and suspensions for intranasal administration, suppositories,and the like.

1. A method of treating advanced prostate cancer comprisingadministering to a patient having advanced prostate cancer an androgensuppressing amount of a luteinizing hormone releasing hormone agonistanalog and an amount of calcitriol sufficient to enhance theeffectiveness of luteinizing hormone releasing hormone agonist analogagainst the advanced prostate cancer relative to treatment withluteinizing hormone releasing hormone agonist analog alone.
 2. Themethod of claim 1 wherein the luteinizing hormone releasing hormoneagonist analog is a nonapeptide or decapeptide having the structure:5-oxo-L-Pro-L-His-L-Trp-L-Ser-L-Tyr-Xaa-L-Leu-L-Arg-Yaa (SEQ ID NO:1),wherein Xaa is a D-amino acid residue or a modified D-amino acidresidue; and Yaa is a modified proline residue or a dipeptide comprisinga proline residue and a modified glycine residue.
 3. The method of claim2 wherein Xaa is a residue selected from the group consisting ofO-t-butyl-D-Ser, D-Leu, D-Trp, 2-methyl-D-Trp, N-benzyl-D-His, and3-(2-naphthyl)-D-Ala.
 4. The method of claim 2 wherein Yaa is a residueselected from the group consisting of N-ethyl-L-prolinamide,L-prolylcarbazamide, L-prolylglycinamide, and N-ethylprolylglycinamide.5. The method of claim 1 wherein the calcitriol is in the form of aninjectable solution comprising about 1 to about 30 micrograms permilliliter of calcitriol in an isotonic saline medium and a sufficientquantity of nonionic surfactant to solubilize the calcitiriol therein.6. The method of claim 5 wherein the nonionic surfactant is apolysorbitan.
 7. The method of claim 6 wherein the quantity of thepolysorbitan is in the range of about 1 to about 10 milligrams permilliliter.
 8. The method of claim 5 wherein the injectable solutionfurther comprises about 1 to about 15 milligrams per milliliter ofascorbic acid.
 9. The method of claim 5 wherein the injectable solutionfurther comprises about 2 to about 6 milligrams per milliliter ofascorbic acid.
 10. The method of claim 5 wherein the injectable solutionfurther comprises about 1 to about 2 milligrams per milliliter ofethylenediamine tetraacetic acid or a salt thereof.
 11. The method ofclaim 5 wherein the injectable solution further comprises about 5 toabout 30 micrograms per milliliter of calcitriol, about 1 to about 15milligrams per milliliter of ascorbic acid, and about 1 to about 2milligrams per milliliter of ethylenediamine tetraacetic acid or a saltthereof, in an isotonic saline medium; and a sufficient quantity ofnonionic surfactant to solubilize the calcitiriol therein.
 12. Themethod of claim 11 wherein the nonionic surfactant is a polysorbitan.13. The method of claim 12 wherein the quantity of the polysorbitan isin the range of about 1 to about 10 milligrams per milliliter.
 14. Themethod of claim 1 wherein the calcitriol is administered weekly at adosage in the range of about 0.1 to about 20 micrograms per kilogram,based on the weight of the patient in kilograms.
 15. The method of claim1 wherein the calcitriol is administered weekly at a dosage in the rangeof about 0.5 to about 10 micrograms per kilogram, based on the weight ofthe patient in kilograms.
 16. The method of claim 1 wherein theluteinizing hormone releasing hormone agonist analog comprisesleuprolide, goserelin, or a salt thereof.
 17. The method of claim 16wherein the leuprolide is administered subcutaneously as a dailyinjection of solution of leuprolide acetate in an isotonic salinesolution at a dosage of about 1 milligram per day.
 18. The method ofclaim 16 wherein the leuprolide, goserelin, or salt thereof is in theform of an injectable, sustained release depot formulation.
 19. Themethod of claim 18 wherein the leuprolide is administered a singleintramuscular injection per week of about 7.5 mg of leuprolide in theform of a sustained-release depot formulation.
 20. The method of claim18 wherein the leuprolide is administered a single intramuscularinjection per month of about 7.5 mg of leuprolide in the form of asustained-release depot formulation.
 21. The method of claim 18 whereinthe leuprolide is administered as a single intramuscular injection everythree months of about 11.75 mg of leuprolide in the form of athree-month, sustained-release depot formulation.
 22. The method ofclaim 18 wherein the leuprolide is administered as a singleintramuscular injection every four months of about 30 mg of leuprolidein the form of a four-month, sustained-release depot formulation. 23.The method of claim 18 wherein the leuprolide is administeredsubcutaneously in the form of a one-year, sustained release implantcontaining about 65 mg leuprolide per implant.
 24. The method of claim18 wherein the goserelin is administered subcutaneously in the form of aone-month sustained release implant containing about 3.6 mg of goserelinper implant
 24. The method of claim 18 wherein the goserelin isadministered subcutaneously in the form of a three-month sustainedrelease implant containing about 10.8 mg of goserelin per implant.